Elevated expression of the receptor tyrosine kinase Axl in pancreatic ductal adenocarcinoma (PDAC) is associated with increased metastasis and shorter survival. Axl participates in malignant progression via tumor cell survival, proliferation, drug resistance, epithelial-to-mesenchymal transition and tumor stromal activation including angiogenesis and tumor-associated macrophage recruitment. Axl is activated by a single ligand, the vitamin K-dependent gamma-carboxyglutamic (GLA) domain protein, Gas6. Aberrant activation can occur through non-ligand mechanisms including homotypic interaction between Axl extracellular domains on adjacent cells, crosstalk with other receptor tyrosine kinases and cytoplasmic tyrosine kinases (e.g., Src family). Inhibition of Axl blocks metastatic activity and enhances drug sensitivity in breast cancer, but the effect of targeting Axl in animal models of PDAC has not been evaluated. Our preliminary studies document that Axl inhibition in pancreatic cancer cells diminishes PI3K-Akt and MAP kinase signaling and strongly reduces primary and metastatic burden in orthotopic models. In the present proposal, we will expand on these studies and evaluate the therapeutic efficacy of three different strategies to abrogate Axl activity in vivo. The central hypothesis of the proposal is that targeting Axl will block PDAC progression and enhance sensitivity to standard-of-care chemotherapy. We will address this hypothesis with the following aims 1) to determine the therapeutic efficacy of inhibiting Gas6 ligand binding to Axl with the clinical vitamin K-dependent carboxylase inhibitor warfarin; 2) to characterize the anti-tumor effects of direct inhibition of Axl signal transduction with novel therapeutics. We have documented that warfarin can reduce Axl activity at doses much lower than those required for anticoagulant activity. We have found that warfarin reduces tumor burden and blocks metastasis in orthotopic models of pancreatic cancer in an Axl dependent manner. We will expand these studies to include evaluation of the efficacy of warfarin in autochthonous models of PDAC. In collaboration with Prof. James Lorens' laboratory (University of Bergen) we will explore the efficacy of a new inhibitory anti-Axl monoclonal antibody, 10C9 and a recently developed oral, small molecule Axl receptor tyrosine kinase inhibitor (BGB324). The therapeutic efficacy of direct Axl inhibition with 10C9 and BGB324 will be tested in relevant in vivo models of pancreatic cancer. Our aims encompass blockade of Gas6-dependent autocrine/paracrine and non-ligand Axl activation. Our overall goal is to document that inhibition of Axl is a viable therapeutic strategy for the treatment of pancreatic cancer and to determine if Axl inhibition combines effectively with current treatment modalities.